Wnt Proteins Are Self-Renewal Factors for Mammary Stem Cells and Promote Their Long-Term Expansion in Culture

ArticleinCell stem cell 6(6):568-77 · June 2010with26 Reads
DOI: 10.1016/j.stem.2010.03.020 · Source: PubMed
Abstract
Adult stem cells have the ability to self-renew and to generate specialized cells. Self-renewal is dependent on extrinsic niche factors but few of those signals have been identified. In addition, stem cells tend to differentiate in the absence of the proper signals and are therefore difficult to maintain in cell culture. The mammary gland provides an excellent system to study self-renewal signals, because the organ develops postnatally, arises from stem cells, and is readily generated from transplanted cells. We show here that adult mammary glands contain a Wnt-responsive cell population that is enriched for stem cells. In addition, stem cells mutant for the negative-feedback regulator Axin2 and therefore sensitized to Wnt signals have a competitive advantage in mammary gland reconstitution assays. In cell culture experiments, exposure to purified Wnt protein clonally expands mammary stem cells for many generations and maintains their ability to generate functional glands in transplantation assays. We conclude that Wnt proteins serve as rate-limiting self-renewal signals acting directly on mammary stem cells.
    • "Subsequently, expansion of Lgr5 + adult stem cells of stomach and liver tissue was also accomplished by using Rspo1 [148,149]. MaSCs can be expanded in vitro under serum-free and feeder-free defined conditions when supplemented with Wnt3a [22]. A subsequent study demonstrated that Wnt4, the endogenous Wnt regulating MaSCs in vivo, can also expand MaSCs in culture [69]. "
    [Show abstract] [Hide abstract] ABSTRACT: The Wnt pathway has emerged as a key signaling cascade participating in mammary organogenesis and breast oncogenesis. In this review, we will summarize the current knowledge of how the pathway regulates stem cells and normal development of the mammary gland, and discuss how its various components contribute to breast carcinoma pathology.
    Full-text · Article · Jul 2016
    • "In many in vitro expansion systems of adult stem cell, both Wnts and mitogenic growth factors are required for sustaining the culture [12,[42][43][44][45] . Wnt proteins are not required for proliferation in these contexts, indicating that inhibition of differentiation is its main function in self-renewal [12,46] . This leads to a simplified view that mitogenic growth factors are responsible for pushing the cells into division. "
    [Show abstract] [Hide abstract] ABSTRACT: Cyclin Y family can enhance Wnt/β-catenin signaling in mitosis. Their physiological roles in mammalian development are yet unknown. Here we show that Cyclin Y-like 1 (Ccnyl1) and Cyclin Y (Ccny) have overlapping function and are crucial for mouse embryonic development and mammary stem/progenitor cell functions. Double knockout of Ccnys results in embryonic lethality at E16.5. In pubertal development, mammary terminal end buds robustly express Ccnyl1. Depletion of Ccnys leads to reduction of Lrp6 phosphorylation, hampering β-catenin activities and abolishing mammary stem/progenitor cell expansion in vitro. In lineage tracing experiments, Ccnys-deficient mammary cells lose their competitiveness and cease to contribute to mammary development. In transplantation assays, Ccnys-deficient mammary cells fail to reconstitute, whereas constitutively active β-catenin restores their regeneration abilities. Together, our results demonstrate the physiological significance of Ccnys-mediated mitotic Wnt signaling in embryonic development and mammary stem/progenitor cells, and reveal insights in the molecular mechanisms orchestrating cell cycle progression and maintenance of stem cell properties.
    Full-text · Article · May 2016
    • "In many in vitro expansion systems of adult stem cell, both Wnts and mitogenic growth factors are required for sustaining the culture [12,[42][43][44][45] . Wnt proteins are not required for proliferation in these contexts, indicating that inhibition of differentiation is its main function in self-renewal [12,46] . This leads to a simplified view that mitogenic growth factors are responsible for pushing the cells into division. "
    Full-text · Article · May 2016
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